MATERIALS AT THE BORDERLINE BETWEEN CHEMISTRY AND LIFE: NANOSTRUCTURES IN DIAGNOSTIC MOLECULAR IMAGING

Materials at the smallest size scales are physicochemical in their structure and interactions. As structures grow larger than a few nanometers their complexity allows regional differentiation, so that for example one part of the structure may serve as recognition motif, a second part may move slightly to permit specific interaction with another structure and a third may bear highly specific information: differentiation within the structure allows it to carry out specific tasks under defined conditions. Enzymes and antibodies are familiar examples a few nanometers in size, but slightly larger structures appear to reach a certain critical complexity that allows multifunctional performance of tasks essential in living cells. Numerous components of the living cell are nanostructures of this size: ribosomes ~30 nm diameter, nuclear pores 145x80 nm, ion channels with 4 nm pore diameter, DNA and RNA ~2 nm strand diameter, several classes of intracellular vesicles 40-60 nm in diameter, elements of the cytoskeleton with strand thicknesses 4 nm, 10 nm or 25 nm, and even cell membranes in one important dimension (thickness: ~10 nm). Extracellular fibres such as collagen, 60 nm in diameter, and many matrix molecules such as glycosaminoglycans with 3 nm diameter chains of 250 nm length, are also in this size range. In one sense, living cells and tissues contain many nano-machines essential for their function. Viruses generally are also in this size range and, although not alive, present a wide repertoire of the behaviours required in the components of living cells as, for example: specific recognition and adhesion (in this case, to a living cell), followed by internal movement leading to injection of physiologically active materials (DNA, RNA) into the cell. This pre-defined sequence of actions mimics events characteristic of living organisms, for example specific recognition and adhesion of ribosomes to mRNA and endoplasmic reticulum followed by movement of the ribosome along the RNA and injection of the newly-formed polypeptide strand into the endoplasmic reticulum. These behaviours, not found in structures smaller than approximately 10 nm, are precisely those which bear a rich potential in the field of diagnostic molecular imaging.

Nanoparticles in the size range 20-200 nm, constructed of materials as different as gold, lipids, proteins, or iron oxide, are under development across the world to carry out specific recognition of molecules characteristic of disease states, and to follow up the specific recognition by insertion of physiologically active agents such as drugs, DNA or RNA into the cells bearing those molecules. The first and simplest such particles are already in use in clinical applications, and a wide range of more highly developed particles is in preparation. All the particles under development are much more primitive than viruses, so a large potential for improvement exists. Our group in Innsbruck, in collaboration Austria- and Europe-wide with several project partners, is interested in enabling one further function not usually found in living cells or viruses: the capacity to signal to doctors the precise location of the particle within the human body. This requires attachment of any of a long list of signalling materials including iron, gadolinium, iodine, gold, dyestuffs, and many more. That this endeavour will succeed is evident because it already works well in Nuclear Medicine. We plan to combine the flexible multi-functionality of nano-machinery with the signalling capacities known in nuclear medicine, with the further aim of achieving this for imaging modalities such as MRI, ultrasound and photo-acoustic imaging. The timeline for realising this potential of, for example, early flagging of cardiovascular disease or of non-symptomatic malignancies, bearing in mind the necessity of avoiding risks such as toxicity, is 10-15 years from now.